Acute brain injury such as traumatic brain injury (TBI) disrupts the normal function of the brain and generally has a poor prognosis for functional recovery and survival. Termed a ‘silent epidemic’, TBI is a leading cause of mortality and morbidity in children, teens and active adults from ages 1 to 44, with an annual incidence of 2.5 million in the US (Coronado et al., J. Safety Res. 43:299-307 (2012)). TBI can lead to acute and potentially long-lasting neurological dysfunction, including the development of chronic traumatic encephalopathy (CTE) or even Alzheimer's disease (Smith et al., Nat. Rev. Neurology 9:211-221 (2013)). A majority of combat-related TBI cases are additionally complicated by a penetrating injury to the brain, which is often even more difficult to manage than non-penetrating injuries (Bell et al., J. Trauma 66:S104-111 (2009)). Despite this substantial socio-economic impact, TBI treatment is limited to palliative care and no specific therapies with long-term benefits are available.
The blood-brain barrier (BBB) is considered a major impediment to systemic treatment of central nervous system (CNS) diseases. As a result, localized delivery of drugs within the brain has been explored, but it has limitations in clinical settings. In acute brain injury and several cerebrovascular diseases, including stroke, hypertension, and ischemia, the BBB is transiently disrupted, which allows extravascular access for macromolecules and neuroprotective drugs from the systemic circulation. In fact, the leakage of serum proteins into brain parenchyma is used to test for BBB integrity (Kuroiwa et al., Acta Neuropathologica 76:62-70 (1988)). However, lack of specific binding of passively accumulating proteins in the injured area can result in low retention and subsequent washout over time. Due to this clearance, the therapeutic efficacy of a systemically administered drug may be greatly limited.
Previous studies have used in vivo phage display to probe tissues in situ for specific molecular signatures and discovered homing peptides specific for different pathologies including tumors, atherosclerotic plaques, and wounds (Ruoslahti, Nat. Rev. Cancer 2:83-90 (2002); Ruoslahti, Adv. Mater. 24:3747-3756 (2012); Teesalu et al., Methods Enzymol. 503:35-56 (2012)). An acute and complex event such as TBI is suited for a similar approach as site-specific molecular changes in protein expression have been reported (Natale et al., J. Neurotrauma 20:907-927 (2003)).
Current approaches for delivering therapeutics to brain injury sites are invasive and can add complications to the injury.
It is an object of the present invention to provide peptides that recognize specific molecular changes at the sites of nervous system injury and enhance delivery of compounds and compositions to such sites.
It is another object of the present invention to provide peptides that selectively home to sites of nervous system injury.
It is another object of the present invention to provide compositions that selectively home to sites of nervous system injury.
It is another object of the present invention to provide methods for selectively targeting sites of nervous system injury.
It is another object of the present invention to provide methods for treating nervous system injury by selectively targeting sites of nervous system injury.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present disclosure as it existed before the priority date of each claim of this application.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.